Gastric secretion in patients with caustic ingestion: A prospective study.

BACKGROUND: Caustic ingestion can lead to structural changes in the upper gastrointestinal tract. However, there are limited data on the effect of caustic ingestion on gastric secretion. This study was planned to determine the changes in gastric acid output in patients with caustic ingestion. METHODS: It was a prospective study done at a tertiary care center in northern India. Twenty consecutive patients in chronic phase of caustic ingestion were evaluated for the study. The gastric secretory function was estimated in the basal state and following pentagastrin stimulation. These results were compared with normal values for our laboratory. RESULTS: The mean age of the included patients (n = 20) was 27.35 ± 2.96 years and 14 patients were male. Sixteen (80%) patients had a history of acid ingestion. Patients with caustic ingestion had significantly lower mean gastric acid secretion (0.8 ± 0.4 mEq/h vs. 4 ± 0.4 mEq/h; p < 0.001) compared to controls. After pentagastrin stimulation, the mean gastric juice volume (31.8 ± 6 mL/h vs. 62.3 ± 11.7 mL/h; p < 0.01) and acidity (15.3 ± 5.1 mEq/L vs. 39.6 ± 9.3 mEq/L; p < 0.001) increased in patients with caustic ingestion, but were lower than those in control subjects. Patients with a lower esophageal stricture (n = 6) had decreased maximum acid output (0.62 ± 0.32 mEq/h vs. 6.05 ± 0.55 mEq/h; p < 0.05) compared to patients with stricture in the upper or middle esophagus. CONCLUSION: Caustic ingestion is associated with reduced gastric juice volume and acid output. Patients with stricture in the lower one third of the esophagus are at a higher risk of hypochlorhydria compared to patients with stricture in either the upper or middle esophagus.

The Phylogeny and Biological Function of Gastric Juice-Microbiological Consequences of Removing Gastric Acid.

Gastric juice is a unique combination of hydrochloric acid (HCl), lipase, and pepsin. Acidic gastric juice is found in all vertebrates, and its main function is to inactivate microorganisms. The phylogenetic preservation of this energy-consuming and, at times, hazardous function (acid-related diseases) reflects its biological importance. Proton pump inhibitors (PPIs) are one of the most widely used drugs in the world. Due to the reduced prevalence of Helicobacter pylori infection as well as the increased use of inhibitors of gastric acid secretion, the latter has become the most important cause of gastric hypoacidity. In the present manuscript, we review the microbiological consequences of removing gastric acidity. The resulting susceptibility to infections has not been studied extensively, and focus has mainly been restricted to bacterial and parasitic agents only. The strongest evidence concerning the relationship between hypochlorhydria and predisposition to infections relates to bacterial infections affecting the gastrointestinal tract. However, several other clinical settings with increased susceptibility to infections due to inhibited gastric acidity are discussed. We also discuss the impact of hypochlorhydria on the gut microbiome.

Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified.

Proton pump inhibitors (PPIs) are common medications within the practice of gastroenterology. These drugs, which act through the irreversible inhibition of the hydrogen/potassium pump (H+/K+-ATPase pump) in the gastric parietal cells, are used in the treatment of several acid-related disorders. PPIs are generally well tolerated but, through the long-term reduction of gastric acid secretion, can increase the risk of an imbalance in gut microbiota composition (i.e., dysbiosis). The gut microbiota is a complex ecosystem in which microbes coexist and interact with the human host. Indeed, the resident gut bacteria are needed for multiple vital functions, such as nutrient and drug metabolism, the production of energy, defense against pathogens, the modulation of the immune system and support of the integrity of the gut mucosal barrier. The bacteria are collected in communities that vary in density and composition within each segment of the gastrointestinal (GI) tract. Therefore, every change in the gut ecosystem has been connected to an increased susceptibility or exacerbation of various GI disorders. The aim of this review is to summarize the recently available data on PPI-related microbiota alterations in each segment of the GI tract and to analyze the possible involvement of PPIs in the pathogenesis of several specific GI diseases.

Comparison of the human gastric microbiota in hypochlorhydric states arising as a result of Helicobacter pylori-induced atrophic gastritis, autoimmune atrophic gastritis and proton pump inhibitor use.

Several conditions associated with reduced gastric acid secretion confer an altered risk of developing a gastric malignancy. Helicobacter pylori-induced atrophic gastritis predisposes to gastric adenocarcinoma, autoimmune atrophic gastritis is a precursor of type I gastric neuroendocrine tumours, whereas proton pump inhibitor (PPI) use does not affect stomach cancer risk. We hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota and that this influenced subsequent tumour risk. 95 patients (in groups representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis and autoimmune atrophic gastritis) were selected from a cohort of 1400. RNA extracted from gastric corpus biopsies was analysed using 16S rRNA sequencing (MiSeq). Samples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. Patients with autoimmune atrophic gastritis also exhibited relatively high microbial diversity, but with samples dominated by Streptococcus. H. pylori colonisation was associated with decreased microbial diversity and reduced complexity of co-occurrence networks. H. pylori-induced atrophic gastritis resulted in lower bacterial abundances and diversity, whereas autoimmune atrophic gastritis resulted in greater bacterial abundance and equally high diversity compared to normal stomachs. Pathway analysis suggested that glucose-6-phospahte1-dehydrogenase and D-lactate dehydrogenase were over represented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase. Autoimmune and H. pylori-induced atrophic gastritis were associated with different gastric microbial profiles. PPI treated patients showed relatively few alterations in the gastric microbiota compared to healthy subjects.

Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption.

PURPOSE: Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria. METHODS: In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule. RESULTS: Pretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole. CONCLUSIONS: The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.

Characteristics of the Human Upper Gastrointestinal Contents in the Fasted State Under Hypo- and A-chlorhydric Gastric Conditions Under Conditions of Typical Drug - Drug Interaction Studies.

OBJECTIVE: Evaluate the impact of reduced gastric acid secretion after administration of two acid-reducing agents on the physicochemical characteristics of contents of upper gastrointestinal lumen of fasted adults. MATERIALS AND METHODS: Eight healthy male adults, fasted from food for 12 h, participated in a three-phase crossover study. Phase 1: No drug treatment prior to aspirations. Phase 2: Oral administration of 40 mg pantoprazole at ~9 am the last 3 days prior to aspirations and at ~7 am on aspiration day. Phase 3: Oral administration of 20 mg famotidine at ~7 pm prior to aspirations and at ~7 am on aspiration day. Samples from the contents of upper gastrointestinal lumen were aspirated for 50 min, after administration of 240 ml table water at ~9 am. RESULTS: Reduction of gastric acid secretion was accompanied by reduced buffer capacity, chloride ion concentration, osmolality and surface tension in stomach and by increased pH (up to ~0.7 units) in upper small intestine during the first 50 min post-water administration. The mechanism of reduction of acid secretion seems to be important for the buffer capacity in stomach and for the surface tension in upper gastrointestinal lumen. CONCLUSIONS: Apart from gastric pH, reduced acid secretion affects physicochemical characteristics of contents of upper gastrointestinal lumen which may be important for the performance of certain drugs/products in the fasted state.

Expression of Tlr2, Defa, Muc2 genes in rat duodenal upon long-term gastric hypacidity and with multiprobiotic correction.

Expression of Tlr2, Muc2, Defa genes in rat duodenal upon long-term gastric hypacidity (hypochlorhydria) and with multiprobiotic correction was investigated. Increasing of Tlr2, Muc2, Defa expression on the background of the intensification of lipid peroxidation in rat duodenal villus and crypt epithelial cells upon gastric hypoacidity was shown. The mRNAs patterns of genes mentioned above were shown to decrease or approach to control values as well as the level of lipid peroxidation products under the treatment of hypoacidic rats with the multiprobiotic. The data obtained may indicate involvement of genes Tlr2, Muc2, Defa in development of inflammation in the duodenum due to dysbiotic changes under conditions of prolonged hypochlorhydria.

The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria.

Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib Cmax and AUC0-∞ by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib Cmax and AUC0-∞ by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions.

Experimental correction of metabolic changes in mouth at long-term hypoacidity by multiprobiotic "Symbiter acidophilic".

It is known, that long decrease in gastric secretion leads to the development of hypergastrinemia, dysbiosis and to pathological changes in digestive organs. Very important there is a search of ways to correction of these undesirable consequences. Long-term usage of omeprazole leads to metabolic disorders in periodontium tissues and salivary glands, such as development of NO-ergic system disbalance and activation of free-radical oxidation, that are positively corrected by multiprobiotic of new generation "Symbiter acidophilic".

Proton pump inhibitor therapy and potential long-term harm.

PURPOSE OF REVIEW: This review summarizes the recent literature on the potential side-effects of proton pump inhibitors (PPIs) and known interactions with the metabolism/absorption of other drugs. RECENT FINDINGS: Data confirm that PPIs are a very well tolerated drug class. Their high safety, efficacy and wide distribution lead to overuse, inappropriate dosage or excessive duration of treatment. Despite the absorption of micronutrients or other plausible effects on the development of bacterial infections linked to PPI-induced hypochlorhydria, it is difficult to demonstrate an association between PPI and specific symptoms. A possible negative effect of PPIs on bone integrity appears weak, but hypomagnesemia is likely a PPI drug class effect. A higher risk of Clostridium difficile infection and other infectious diseases such as small intestinal bacterial overgrowth and spontaneous bacterial peritonitis remain controversial in PPI users. However, the careful use of PPIs in cirrhotic or otherwise fragile patients is mandatory. Short-term or long-term PPI use may trigger microscopic colitis, and the management of this condition may include PPI withdrawal. The effect of PPIs on stimulating exocrine or endocrine gastric cell proliferation is poorly understood. A diagnostic delay or masking of diseases such as gastrinoma is difficult to evaluate. SUMMARY: Short-term standard dose PPI treatment is low risk. Long-term PPI use may complicate health conditions by various mechanisms linked to PPIs and/or to hypochlorhydria.

Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria.

Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (± 0.5) units from 5.2 (± 0.5) to 0.6 (± 0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (± 4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (± 33) and 77 (± 30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions.

[Stress-responsive systems in the rat pancreas upon long-term gastric hypochlorhydria and administration of multiprobiotic "Symbiter"].

The intensity of free-radical processes upon long-term omeprazole-induced hypoacidity in the rat pancreas was investigated. Significant violation of oxidative-antioxidative balance in pancreatic tissue upon gastric hypochlorhydria was established: overproduction of superoxide anion, quantitative changes of lipid functional groups, increased level of lipid peroxidation products, augmentation of xanthine oxidase, superoxide dismutase and glutathione transferase activity, as well as depletion of catalase, glutathione peroxidase activity and reduced glutathione content. The inflected expression of Cckbr gene in the rat pancreas upon these conditions was also observed, thus suggesting an increased risk of pathological changes development in the gland. Abovementioned parameters were only partially restored to control values in the case of simultaneous administration of multiprobiotic "Symbiter" with omeprazole, thus indicating the ability of this preparation to efficiently counteract the development of oxidative damages in pancreatic tissues upon long-term hypoacidic conditions.

A combination of a dairy product fermented by lactobacilli and galactooligosaccharides shows additive effects on mineral balances in growing rats with hypochlorhydria induced by a proton pump inhibitor.

This study aimed to investigate the effects of a combination of a dairy product fermented by lactobacilli (DFL) and galactooligosaccharides (GOS) on mineral balances in growing rats with hypochlorhydria induced by a proton pump inhibitor (PPI). Three-week-old male rats were assigned to receive one of six diets: a control diet, control diets containing 1.6 or 5.0 % GOS, a DFL diet and DFL diets containing 1.6 or 5.0 % GOS for 9 days. From day 5 of the feeding period, half of the rats fed with control diets were subcutaneously administered with saline, whereas the remaining rats were administered with PPI for 5 days. Calcium (Ca), phosphorus (P), magnesium (Mg), iron (Fe) and zinc (Zn) balances were determined from days 6 to 9. PPI administration significantly decreased the apparent absorption of Ca and Fe and increased urinary P excretion, resulting in decreased Ca, Fe and P retention. GOS dose-dependently increased the apparent absorption of Ca, Mg and Fe and urinary Mg excretion and decreased urinary P excretion. DFL significantly increased the apparent absorption of Ca and Mg and urinary Mg excretion. The combination of DFL and GOS additively affected these parameters, resulting in increased Ca, P and Fe retention, and it further increased the apparent absorption and retention of Zn at 5.0 % GOS. In conclusion, the combination of DFL and GOS improves Ca, P and Fe retention in an additive manner and increases the Zn retention in growing rats with hypochlorhydria induced by PPI.

[Influence of oxidative stress on the level of genes expression Tgfb1 and Hgf in rat liver upon long-term gastric hypochlorhydria and administration of multiprobiotic Symbiter].

Free-radical processes upon long-term omeprazole-induced gastric hypochlorhydria in the rat liver were researched. Intensification of oxidative processes in the liver tissue upon gastric hypoacid state was established: overproduction of superoxide anion, hydrogen peroxide, the quantitative changes of lipid functional groups, increased level of lipid peroxidation products, and augmentation of xanthine oxidase activity. The expression of Tgfb1 gene increased, while the expression of Hgf gene was not detected upon long-term suppression of gastric acid secretion of hydrochloric acid by omeprazole that indicated possible development of liver fibrosis. Abovementioned parameters were only partially restored to control values in the case of simultaneous administration of multiprobiotic "Symbiter acidophilic" concentrated with omeprazole, thus indicating the ability of this preparation to counteract the development of oxidative damages in liver tissues upon long-term gastric hypoacidic conditions.

Improved dissolution and pharmacokinetic behavior of dipyridamole formulation with microenvironmental pH-modifier under hypochlorhydria.

The present study aimed to develop and characterize new formulations of dipyridamole (DP), a pH-dependent poorly soluble drug, employing an acidic pH-modifier for improving dissolution and absorption under hypochlorhydric condition. Granule formulations of DP (DPG) with and without fumaric acid (FA) were prepared with wet granulation, physicochemical properties of which were characterized focusing on morphology, dissolution and stability. Pharmacokinetic profiling of orally dosed DPG or DPG with 60% loading of FA (DPG/FA60) was carried out in omeprazole-treated rats as a hypochlorhydric model. Although pH-dependent dissolution behavior was observed in DPG, DPG/FA exhibited high rate and extent of dissolution in both acidic and neutral media. Complete supersaturation was achieved with a 2 h testing period in pH6.8 medium, and co-existing fumaric acid had no impact on the chemical/photochemical stability of DP in solid-state. After oral administration of DPG or DPG/FA60 (10 mg-DP/kg), there was ca. 40% reduction of AUC(0-3) for DPG in omeprazole-treated rats as compared to that in normal rats; however, AUC(0-3) for DPG/FA60 under hypochlorhydria was almost identical to that of DPG in normal rats. Given the improved systemic exposure early after oral administration in hypochlorhydric rats, the DPG/FA might provide better clinical outcomes in hypochlorhydric patients.

Using absorption simulation and gastric pH modulated dog model for formulation development to overcome achlorhydria effect.

Impaired absorption of weakly basic drugs in patients with reduced gastric acidity can lead to loss of efficacy of the therapeutic agent. Hence, a robust formulation which can provide adequate exposure in achlorhydric patients is imperative to achieve the desired efficacy. In this report, formulation development of a weakly basic Merck compound A is described. Compound A shows lower solubility at higher pH and thus is prone to reduced exposure under conditions of achlorhydria, as the compound's solubility increases only in environments of less than pH 2. Several formulations with or without an acidifier were developed and characterized by in vitro dissolution and in gastric pH modified dog model to assess their bioperformance in high gastric pH conditions. To predict the bioperformance of these formulations in humans, a dissolution based absorption model was developed and validated against the observed PPI-interaction data in the clinic and the gastric pH-adjusted dog data. An additional absorption model was developed to allow for incorporation of the dog PK data to provide translation of preclinical to clinical exposure. Based on the in vitro dissolution, in silico absorption modeling and preclinical in vivo data, a citric acid-based formulation (F2) was selected for a human pharmacokinetic study. This study showed that exposures from F2 were not meaningfully different in the presence of proton pump inhibitor (PPI) as compared to non-PPI, thus confirming that the F2 formulation was successful in overcoming the achlorhydria effect. These efforts also highlighted that the complementary use of in vitro/in silico/in vivo (IVISIV) tools may be a helpful strategy in the development of formulations to overcome the achlorhydria effect and achieve adequate exposure in patients with high gastric pH.

Inhibitors of gastric acid secretion increase the risk of prion infection in mice.

UNLABELLED: Gastric juice is a unique combination of hydrochloric acid and the proteolytic enzyme pepsin. Its main function is to inactivate ingested microorganisms. Prions cause fatal transmissible degenerative encephalopathies in animals and man. These diseases have attracted attention due to the proposed link between bovine spongiform encephalopathy in cattle and the occurrence of a new variant Creutzfeldt-Jakob disease in humans where the most probable route of transmission is via contaminated food. The role of gastric juice in the protection against these agents is not settled. OBJECTIVE: The aim of this study was to examine if drug-induced gastric hypoacidity increases the susceptibility of prion infection transmitted by the oral route. MATERIAL AND METHODS: Forty-six mice (tg338) were given brain homogenates contaminated with scrapie by gastric intubation. Twenty-two of these animals were concomitantly dosed with omeprazole increasing the median gastric pH from 1.2 to 5.3. After 381 days, the animals were sacrificed and all the brains were examined for detection of pathogenic prion proteins by enzyme-linked immunosorbent assay and western blot. RESULTS: Drug-induced decrease in gastric acidity more than doubled the rate (59% vs. 25%, p < 0.035) of brain infection compared to controls with normal gastric acidity at the time of inoculation. CONCLUSIONS: Our results demonstrate that the normal gastric juice constitutes a significant defense against prion disease in mice. Thus, gastric hypochlorhydria would be expected to enhance the susceptibility to prion infection by the oral route. This finding may have relevance to the pathogenesis of the new variant Creutzfeldt-Jakob disease and prion diseases in general.

[Pathogenesis, treatment, and prevention of erosive-ulcerative lesions in the mucous membrane of the upper digestive tract].

The authors present results of examination and treatment of 698 patients with erosive-ulcerative lesions in the mucous membrane of the upper digestive tract that accounted for 39.49% of all subjects with gastrointestinal hemorrhage. These lesions were diagnosed in 73.8% of the patients in critical conditions. The leading role in their pathogenesis is played by ischemic-perfusion syndrome, gastric acid hypersecretion resulting in microcirculatory disorders, hypoxia, and activation of free radicals in gastric and duodenal mucosa. It is concluded that preventive and conservative therapy of the above lesions must be focused on the correction of ischemia and after-effects of reperfusion to achieve long-standing hypoacidic state (pH < 4) with the help of up-to-date antisecretory agents.

[Chronic use of proton pump inhibitors: is the risk of osteoporosis and fractures real?]. / ¿Es real el riesgo de osteoporosis y riesgo de fracturas con el uso crónico de inhibidores de la bomba de protones?

Proton pump inhibitors (PPI) are one of the most widely used groups of drugs and their potential toxicity is periodically reviewed, emphasizing aspects originally considered secondary. The present review analyzes the physiological and pharmacological bases and the scarce clinical evidence for a potential association between the continued administration of PPI and the development of osteoporosis and bone fractures. Both disorders are clearly related to calcium homeostasis and are highly important in elderly patients due to their poor general prognosis and disabling consequences.